The toll of advanced breast cancer on women's lives remains unacceptably high and new approaches are needed to treat this disease. The purpose of this proposal is to investigate a novel cell surface receptor that orchestrates pericellular protease activities and thus, modulates the tumor microenvironment, and to test whether this receptor may serve as a therapeutic target in advanced breast cancer. The broad, long term goal of this proposal is to identify new mechanisms for treating late-stage breast cancer. This proposal is based on our discovery of a new protein, the plasminogen receptor, Plg-RKT, which promotes activation of plasminogen to the broad spectrum protease, plasmin. Cell surface plasmin regulates the tumor microenvironment by effecting degradation of the ECM and release of growth factors from the ECM. Our preliminary data show that Plg-RKT is highly expressed in human invasive ductal carcinoma and metastatic human breast tumor cell lines. Furthermore, our function blocking anti-Plg-RKT mAb reduced lung metastases in a xenograft model of human breast cancer. Interestingly, in a previously published genome-scale quantitative image analysis, overexpression of more than 86 cDNAs, including the Plg-RKT cDNA, resulted in dramatic increases in cell proliferation whereas knockdown of Plg-RKT mRNA resulted in apoptosis, underscoring the oncogenic potential of this gene product. In microarray studies, Plg-RKT mRNA expression had a high power to predict cervical lymph node metastasis in oral squamous cell carcinoma. The central hypothesis to be addressed in this proposal is that Plg-RKT is a missing link that acts in synergy with other components of the plasminogen activation system to modulate the tumor microenvironment in breast cancer progression. To address our hypothesis, our specific aims are: 1) to determine the role of Plg-RKT in mammary gland remodeling and mammary tumor progression; 2) to identify specific mechanisms by which Plg-RKT regulates growth and metastasis of human breast cancer; 3) to evaluate Plg-RKT as a potential target in advanced breast cancer. Studies will be performed in breast tumor cell-based assays in vitro and in vivo using novel function-blocking anti-Plg-RKT antibodies and a new Plg-RKT knockout mouse model. We will determine expression of Plg-RKT in microarray studies of human breast cancer and assess the therapeutic potential of anti-Plg-RKT antibody in preclinical studies. We expect that performance of our specific aims will implicate Plg-RKT as a major new therapeutic target in advanced breast cancer.